The chemical responsible for Viagra's action has precursors with antioxidant applications that go far beyond the erectile tissue, says Nutracon keynote speaker Louis J Ignarro, PhD. His seminal research is leading many product developers to study nitric oxide applications
A 1998 Nobel Prize winner in Medicine for his discoveries related to nitric oxide both as a vasodilator and neuro-transmitter, Louis J Ignarro, PhD, is a professor and research scientist in the department of molecular and medical pharmacology at UCLA School of Medicine in California.
When Ignarro first began studying nitric oxide (NO) in 1978, few envisioned its significance. Ignarro's research has already paved the way for the development of Viagra. His research has elicited an avalanche of research activities in laboratories around the world and has potentially major significance in the treatment of cardiovascular disease, cancer, arthritis, impotence, inflammatory diseases as well as product development potential in sports nutrition. He is also consultant to a number of nutraceutical and pharmaceutical companies.
Here, Ignarro talks to FFN's science editor, Todd Runestad, about his research discoveries related to nitric oxide and how these findings are leading to product developments in the supplements and cosmeceuticals markets.
FI: In being awarded the 1998 Nobel Prize in medicine, what were the key discoveries related to nitric oxide as a vasodilator and neurotransmitter?
Louis Ignarro: This all centres on nitric oxide. The very first experiment we did, in the late-1970s, was with nitro-glycerine, which had been used for 150 years to treat heart pain, or angina, and we revealed its mechanism of action. The way in which the drug worked was not known. We knew it did not work by its explosive properties! As it turns out, it's metabolised in the vascular smooth muscle to nitric oxide. It's tri-nitro-glycerine; one of those nitro groups is simply metabolised to NO. Having found that, we studied the pharmacology of nitric oxide. That's when we found it was a potent vasodilator, it was a potent inhibitor of blood clotting by inhibiting platelet function. The way it inhibits blood clotting is to prevent platelet stickiness, platelet aggregation and platelet adhesion to the inside of the blood vessel lining. Once you block that, you can prevent blood clotting. Nitric oxide is made by the vascular endothelial cells, which line all arteries and veins. It's a protective mechanism. The blood vessels make the NO, the NO diffuses out, and as long as you have a normal healthy endothelial layer, in other words a normal healthy artery, you're going to protect against blood clots. This means you are going to protect against heart attacks, which are blood clots in the coronary arteries, and you're going to protect against stroke, which are blood clots in the brain.
But the key finding was in 1986 when we showed that our own bodies make nitric oxide, and that's mainly the reason I received the award. My lab demonstrated that our vascular system actually makes nitric oxide, it doesn't have to come from nitro-glycerine, and we make it ourselves. After the recognition of all that, the Nobel committee decided to award the Nobel Prize.
The other discovery was its neurotransmitter effects. We discovered in 1990 that nitric oxide is the neurotransmitter in the nerve that runs to the erectile tissue. Before that the neurotransmitter was unknown, that's why there were no useful drugs to treat impotence. Based on our discovery that NO was the neurotransmitter, some bright scientists at Pfizer developed Viagra. So Viagra comes directly from those initial discoveries.
FI: There are other implications with NO beyond impotence and cardiovascular conditions that include arthritis, cancer and sports nutrition. What's the common thread?
LI: The common thread is part of the title of the Nobel Prize, which was "Nitric oxide is a very widespread signalling molecule." Scientists believe today that it's the most widespread signalling molecule. It plays a role in everything. It can increase blood flow, and it acts as an antioxidant. Most people don't know this. And I would like the people in the nutritional field to know this. Nitric oxide is a far more potent antioxidant than alpha-lipoic acid, vitamins C and E, coenzyme Q10, you name it. Probably the most important antioxidant in the body to protect against oxidative stress is nitric oxide. Because of that, it can be used to prevent or treat diseases that are caused by oxidative stress. Arthritis is one of those.
You always see an upregulation or increased formation of nitric oxide during oxidative stress conditions in the body, which can cover so many different diseases. So, that's important. It acts as an antioxidant, it is a vasodilator, and because of its chemistry it can target a number of different key enzymes in the body, which may be useful in preventing the growth of tumour cells by a totally different mechanism. NO slows down the growth of many different kinds of cells, both tumour and normal cells. And we're still working on that mechanism.
FI: There's some evidence that while NO is good for vascular function, unregulated NO overproduction is implicated in part in joint inflammation. Can you modulate the balance, favouring the upside and minimising the downside, through nutritional strategies?
LI: That's a very big misconception. It is not true that nitric oxide excess produces joint inflammation. The evidence people cite is that when people have measured nitric oxide in joint inflammation, they have found an increase. That does not prove cause and effect. What we know now is that the nitric oxide is up as a part of a protective mechanism by the body to cut back on that joint inflammation. What causes the inflammation is in a way partly due to NO but it's mainly due to oxygen radicals. This is a really important point for this whole industry.
Remember I said earlier nitric oxide is an antioxidant? That's true, and there's no problem there when the amounts of NO and the amounts of oxygen radicals are in the low physiological range. But when the body is making huge amounts of NO, like in arthritis—which is also characterized by oxidative stress, so that joint is making huge amounts of oxygen radicals and huge amounts of NO—when the NO reacts to the oxygen radicals, that reaction forms a new product. At low concentrations this new product is not harmful but at higher concentrations it can cause joint destruction. That's called peroxi-nitrite. Many companies I consult for have been directing their efforts recognising that the best way to deal with this situation is to give antioxidants. There has not been enough attention paid by the pharmaceutical industry to develop a potent antioxidant. We don't need more vitamins C and E, we need some new compounds. I wish we could find naturally occurring compounds that are more potent than vitamin C and E.
FI: Are there any?
LI: They're out there. I would maintain that if someone would take a combination of antioxidants, what you're going to do is remove most of those oxygen radicals in and around the joint. Now, you're not going to have a toxic effect of nitric oxide because you're still going to have that NO but now that NO is not reacting with the oxygen radicals, the NO is free by itself to exert a protective anti-inflammatory effect. There are dozens of papers showing that nitric oxide is a potent anti-inflammatory agent. But if you mix NO with oxygen radicals, you don't have that, instead you have a pro-inflammatory effect, due to the peroxi-nitrite.
FI: So the body is producing the nitric oxide in a joint condition to counteract the inflammatory chemicals it's releasing?
LI: Yes, what I usually call a reflex protective effect. That's what many of us think.
FI: So the confusion lies where people see the body is producing a lot of NO in a joint condition so they think it must be the NO?
LI: Many scientists need to take a hard look at that. That's the danger of a drawing conclusions from descriptive data. Just because it's up does not mean it's causing anything harmful.
FI: Moving beyond orally taken nutraceuticals, what about modulating the NO axis as a viable pursuit in skin-care products?
LI: I am a consultant for L'Oreal and their Lancôme division in the cosmeceutical industry. They have one NO-related product out and another that just launched in January. Remember how I said NO was a widespread signalling molecule? Guess what? The major molecule in the skin that causes tanning is nitric oxide. That was a beautiful finding when they discovered it a couple years ago.
When UV light shines on your skin, one of the things it stimulates is increased nitric oxide production, and the nitric oxide stimulates these cells called melanocytes to release melanin, which is the dark pigmentation. And you can completely block that if you block nitric oxide synthesis. In Asia they like to whiten their skin; in the US we like to make our skin darker and get a nice tan. So L'Oreal has developed a product that inactivates nitric oxide once it's rubbed on the skin so it makes your skin whiter but very importantly it gets rid of blotches and all kinds of marks. And they're working on a product where they stimulate tanning the natural way, that is by giving nitric oxide into the skin. Because then you won't get a yellowing effect, like with most products that are actually chemicals that cause a discoloration, and so what better way to cause natural skin tanning than to stimulate the melanogenesis itself?
Louis J Ignarro, PhD, is the keynote speaker at Nutracon 2004 on Friday, March 5, at 8:30 am at the Anaheim Convention Center, Anaheim, California. More information: www.nutraconference.com